Preclinical and clinical evidence implicate the serotonin ((5-HT) transporter site in the pathophysiology and treatment of major depression. Drugs with potent and selective inhibitory action on the 5-HT transporter are effective antidepressants. Most, but not all studies have reported a reduced density of platelet 5-HT transporter sites in drug free depressed patients. Direct assessment of brain 5-HT transporter receptor density in living human subjects has been limited by the lack of brain imaging techniques capable of accurately measuring these sites. Our research group and others have developed and validated the accuracy of single photon computerized tomography (SPED to examine 5-HT transporter sites in human and nonhuman primate brain using [123I]beta-CIT. These investigations have demonstrated infusion of [123I]beta-CIT results in a concentration of activity in striatum and hypothalamic/midbrain regions. Pharmacological characterization of this brain uptake of [123I]beta-CIT indicate that uptake in the striatum and hypothalamic/midbrain regions are associated primarily with dopamine and 5-HT transporter sites, respectively. The specific aims of the current proposal are as follows: A. To determine if the binding of [123I]beta-CIT midbrain serotonin (5-HT) transporter sites are decreased in drug free patients with major depression compared to healthy control subjects. The midbrain binding of the 5-HT transporter will be measured using SPECT and [123I]beta-CIT. The outcome measure for midbrain 5-HT transporter binding will be V3", which is the ratio of specific to nonspecific brain uptake under equilibrium binding conditions. B. To determine if there is a significant positive correlation between midbrain 5-HT transporter binding and platelet 5-HT transporter density in drug free depressed patients and healthy subjects. This will be done by examining the relationship between midbrain binding of [123I]beta-CIT and platelet 3H-paroxetine binding in depressed patients and healthy control subjects. C. To determine the percent occupancy of the midbrain 5-HT transporter that occurs with therapeutic doses of the selective serotonin reuptake inhibitor antidepressant, paroxetine. This will be done by measuring the reduction in midbrain binding of [123I]beta-CIT following 14 days of paroxetine administration with 20 mg daily, a time period by which steady state plasma levels have been achieved. D. To obtain preliminary data relevant to the question of whether there is a relationship between midbrain 5-HT transporter binding and therapeutic response to paroxetine. This will be done by also imaging the depressed patients after 8 weeks of paroxetine treatment when the presence or absence of a therapeutic remission will be determined. The midbrain binding of [123I]beta-CIT obtained at baseline, after 2 weeks and 8 weeks of paroxetine treatment will be related to therapeutic response.